Device and Method for Electroporation Based Treatment of Stenosis of a Tubular Body Part

ABSTRACT

The present invention relates to medical devices and methods for treating a lesion such as a vascular stenosis using non-thermal irreversible electroporation (NTIRE). Embodiments of the present invention provide a balloon catheter type NTIRE device for treating a target lesion comprising a plurality of electrodes positioned along the balloon that are electrically independent from each other so as to be individually selectable in order to more precisely treat an asymmetrical lesion in which the lesion extends only partially around the vessel.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application relies on the disclosure of and claims priority to andthe benefit of the filing date of U.S. Provisional Application No.61/508,251, filed Jul. 15, 2011, the disclosure of which is herebyincorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to medical devices and methods fortreating, reducing, or preventing stenosis using non-thermalirreversible electroporation. Embodiments of the present inventionprovide balloon catheter devices for treating or preventing stenosiscomprising a plurality of electrodes for selectively and irreversiblyelectroporating a portion of the inner circumference of a tubularstructure within the body. Such devices, systems and methods areparticularly useful for treating asymmetrical stenosis.

2. Description of Related Art

Atherosclerosis is the main cause of heart attack, stroke and gangreneof the extremities. See Burt H M, Hunter W L (2006), Drug-elutingstents: a multidisciplinary success story, Adv Drug Deliv Rev 58:350-357 (“Burt 2006”); and Lusis A J (2000) Atherosclerosis, Nature 407:233-241 (“Lusis 2000”). Three different processes have been identifiedin studies of animals with induced hypercholesterolaemia that arethought to participate in the formation of atherosclerotic lesions: 1)proliferation of smooth muscle cells, macrophages and lymphocytes; 2)the formation by smooth muscle cells of a connective tissue matrixcomprising elastic fiber proteins, collagen and proteoglycans; and 3)accumulation of lipid and mostly free and sterified cholesterol in thesurrounding matrix and the associated cells. See Ross R (1993), Thepathogenesis of atherosclerosis: a perspective for the 1990s, Nature362: 801-809.

The introductions of balloon angioplasty and stent implantation in thecoronary arteries have reduced significantly the fatalities associatedwith this disease, however, coronary artery restenosis and neointimalhyperplasia remain clinical problems. See Lusis 2000; and Al Suwaidi J,Berger P B, Holmes D R, Jr. (2000) Coronary artery stents, Jama 284:1828-1836. Millions of people are affected by atherosclerosis. Onefeature of this disease is stenosis, which is defined as an abnormalnarrowing or contraction of a tubular body part such as arteries, veins,non-vascular ducts and other tubular structures such as urethra,fallopian tubes, esophageal, bronchial passages, and the like. Stenosiscauses decreased blood flow through the vessel. A common treatment forstenosis is bypass surgery with less invasive procedures, such asangioplasty procedures like PTA (percutaneous transluminal angioplasty)also available. Angioplasty involves inserting a balloon catheter intothe body to the location of the stenosis, then inflating the balloonagainst the lesion, and applying pressure to compress the lesion andwiden or restore the inside diameter of the blood vessel to restoreblood flow. Variations of PTA procedures have been used to treatperipheral arterial stenosis, coronary lesions and other non-vasculartubular structures such as biliary ducts.

Although PTA treatments find success in restoring blood flow, suchsuccess may be limited or temporary under certain circumstances. Forinstance, it has been found that anywhere from three to six monthsfollowing the angioplasty procedure about half of those treated with PTAdevelop a re-narrowing or occlusion of the vessel, referred to asrestenosis. While the original blockage is formed by plaque deposits onthe vessel wall, restenosis is caused by growth of smooth muscle cellsof the treated artery after angioplasty. It is the trauma imposed on thevessel wall during angioplasty itself that is the cause of restenosis.More particularly, the body reacts to the angioplasty procedure as aninjury and produces scar tissue as cells regenerate on the inner wall ofthe blood vessel in response to the procedure. It is overgrowth of thesecells that causes the restenosis, which is the recurrence of stenosisafter the PTA procedure. A second angioplasty procedure or bypass arecommon treatments for restenosis, but each of these exposes the patientto additional risks. This is because the angioplasty procedure is oftena temporary fix as it will retraumatize the vessel wall—resulting in therecurrence of smooth muscle cell proliferation. Adding furthercomplexity to the issue, restenosis often presents itselfasymmetrically, characterized by cellular regrowth on only portions ofthe circumference of the vessel wall. It has been found that eccentricand polypoid narrowings are not amenable to treatment with PTA alone.See Becker G J, Katzen B T, Dake M D, Noncoronary angioplasty, Radiology1989; 170:921-940.

In attempts to limit the amount of restenosis after angioplasty, effortshave been made to reduce the trauma associated during treatmentprocedures for stenosis. Such efforts include using balloon cathetersequipped for cutting or excising the lesions or in combination with anendomyocardial biopsy device. These efforts, however, have not provenany greater success over conventional angioplasty techniques inpreventing restenosis after surgery.

Post-angioplasty approaches for reducing restenosis have also beenpursued. One such technique involves implanting drug-eluting stentscomprising compositions for suppressing the growth of scar tissue. Thesetechniques have been known to reduce restenosis but are not preferreddue to complications, such as localized blood clots after elution of thedrug, stent fracture, or other long-term implant issues. Most notablerisk factors with stents concern the arterial wall injury that isgenerated with the implantation of the stent and the pressure applied bythe balloon. In-stent restenosis after bare-metal stent (BMS) placementresults in an aggressive healing response (neointimal hyperplasia) thatcauses vascular narrowing. See Burt 2006; Legrand V (2007), Therapyinsight: diabetes and drug-eluting stents, Nat Clin Pract Cardiovasc Med4: 143-150; and Ward M R, Pasterkamp G, Yeung A C, Borst C (2000)Arterial remodeling, Mechanisms and clinical implications, Circulation102: 1186-1191.

Still others have used angioplasty combined with a technique referred toas non-thermal irreversible electroporation. The IRE approach generallyinvolves treatment of the cells subjected to angioplasty to atherapeutic electric field. The goal is to target the vascular cells toablate and kill the cells without causing thermal or mechanical damage.This approach selectively kills the target cells while avoiding damageto the structure of the artery and surrounding tissue. Restenosis isthus avoided or reduced because the targeted vascular cells are killed,which then do not have the capability of forming scar tissue(neointimal).

Generally, irreversible electroporation (IRE) is a minimally invasivetechnique to ablate undesired tissue. See Davalos R V, Mir L M, RubinskyB (2005), Tissue ablation with irreversible electroporation, Annals ofBiomedical Engineering 33: 223-231 (“Davalos 2005”). Maor and colleaguesshowed that IRE reduces the vascular smooth muscle cells population ofmajor blood vessels without affecting the extracellular matrix, which iscrucial in the treatment of coronary artery disease. See Maor E, IvorraA, Leor J, Rubinsky B (2007), The effect of irreversible electroporationon blood vessels, Technology in Cancer Research and Treatment 6:307-312. The procedure involves delivering a series of low energy(intense but short) electric pulses to the targeted tissue. These pulsespermanently destabilize the cell membranes of the treated tissue andcause cell death. IRE has been shown to be an effective means of tissueablation that does not require drugs, and creates no secondary thermaleffects thereby, preserves extracellular matrix, micro-vasculature andnerves. See Rubinsky B (2007), Irreversible Electroporation in Medicine,Technology in Cancer Research and Treatment 6: 255-260. Furthermore, IREablates tissue with sub-millimeter resolution and the treated area canbe imaged in real-time using ultrasound, or other imaging techniquessuch as Magnetic Resonance Imaging, Computed Tomography and/orIntravascular Ultrasound (IVUS).

More particularly, as a result of being exposed to the IRE electricfield, the pores of the target cells are opened to a degree beyond whichthey can recover and the cells die. Concerning restenosis in particular,with fewer cells remaining on the vascular wall after the angioplastyprocedure, the cells are unable to grow thus preventing restenosisaltogether, or the cells which are limited in number can only experiencea limited amount of cellular regrowth thus reducing the amount ofrestenosis. IRE can be performed before, during, and/or afterangioplasty. In some cases, the IRE is preferably performed beforerestenosis occurs, e.g., before angioplasty to treat tissue that willlater be exposed to an angioplasty procedure.

It has been known to use IRE on blood vessels using plate electrodesplaced around the carotid artery to apply the electric pulses. See Maor,E., A. Ivorra, J. Leor, and B. Rubinsky, The Effect of IrreversibleElectroporation on Blood Vessels, Technol Cancer Res Treat, 2007, 6(4):p. 307-312; Maor, E., A. Ivorra, J. Leor, and B. Rubinsky, Irreversibleelectroporation attenuates neointimal formation after angioplasty, IEEETrans Biomed Eng, 2008, 55(9): p. 2268-74; and Maor, E., A. Ivorra, andB. Rubinsky, Non Thermal Irreversible Electroporation: Novel Technologyfor Vascular Smooth Muscle Cells Ablation, PLoS ONE, 2009, 4(3): p.e4757. Unfortunately, this electrode design is highly invasive andrequires the physical exposure of the targeted vessel in order to treatit.

In other existing IRE procedures for treatment of restenosis, the entirecircumference of the vessel wall is exposed to the IRE electric field.In such designs it has been known to use an electrode with positive andnegative independent conducting surfaces, which are energized in anall-or-nothing system, energizing the entire circumference of theelectrode at the same time and with equal energy delivery. Such anapproach is not desirable for cases of asymmetrical restenosis, however,where only a portion or less than the entire circumference of the vesselwall is diseased. In treating asymmetric restenosis with circumferentialIRE, vascular cells on non-diseased portions of the vessel wall areunnecessarily destroyed.

Thus, it is apparent that there is a need for less invasive, lesstraumatic treatment procedures for treating, reducing, or preventingrestenosis. Especially needed are procedures capable of targeting onlythe diseased portions of the vascular structure, or capable of targetingonly portions of the vascular structure susceptible to restenosis, suchas tissue previously subjected to stenosis treatment and/or stenotictissue prior to treatment.

SUMMARY OF THE INVENTION

To this end, embodiments of the present invention provide devices,systems, and methods for treating lesions such as vascular stenosisincluding restenosis. Especially preferred are such devices, systems,and methods for treating asymmetric lesions, i.e., lesions that extendsonly partially around the vessel.

Non-thermal irreversible electroporation (NTIRE) treatment methods anddevices of the invention include a plurality of electrodes positionedalong a balloon of a balloon catheter that are electrically independentfrom each other so as to be individually selectable in order to moreprecisely treat an asymmetrical lesion.

According to one aspect of the present invention, a method of treating astenosis of a tubular body part by non-thermal irreversibleelectroporation is provided. The method involves: inserting, through thetubular body part, a balloon catheter having at least three electrodespositioned and spaced apart along the balloon, the electrodes beingelectrically independent from each other; expanding the balloon to bringthe electrodes near a stenosis to be treated; determining whichelectrodes are near the stenosis; and applying electrical pulses to theelectrodes according to the determination of which electrodes are nearthe stenosis, the applied pulses being in an amount which is sufficientto induce irreversible electroporation of cells of the stenosis, butwhich is insufficient to induce thermal damage to substantially all ofthe cells of the stenosis such that substantially all stenosis cells arekilled by non-thermal irreversible electroporation.

In another aspect of the invention, an entire circumferential area of avessel can be treated by selectively energizing selected conductivesurfaces of an electrode, i.e., delivering the electrical chargeasymmetrically with respect to the vessel, however, selection of theconductive surfaces can be rotated for example sequentially to cover awhole circumferential section of a vessel. In such embodiments, sincesmaller segments of the electrode are being activated at certain times,less power is needed and developing electronics for this would be lesscomplex task.

In another aspect of the invention, the step of applying electricalpulses includes selecting at least one electrode to which the electricalpulses are not to be applied.

In another aspect of the invention, the step of applying electricalpulses includes connecting through a switch a pulse generator output toany pair of the electrodes independent of the other electrodes.

In another aspect of the invention, the step of applying electricalpulses includes control the switch to output the electrical pulses toonly those electrodes that have been selected based on a determinationof which electrodes are near the stenosis.

In another aspect of the invention, the method further comprisesdetermining at least one individualized electrical parameter for eachpair of electrodes based on the determination of which electrodes arenear the stenosis.

In another aspect of the invention, the electrical parameter includesVoltage or pulse duration.

In another aspect of the invention, the method further comprisesdetermining at last one individualized electrical parameter for eachpair of electrodes based on the depth and proximity of the stenosis inrelation to the electrode positions.

In another aspect of the invention, the method includes determining anindividualized voltage level to use for each pair of electrodes based onthe depth of the restenosis near the each pair.

In another aspect of the invention, which electrodes are near thestenosis is determined by one or more imaging markers disposed near theelectrodes.

In another aspect of the invention, the imaging markers include aradiopaque marker capable of rendering an image on any imaging modality,such as CT or IVUS.

In another aspect of the invention, which electrodes are near thestenosis is determined by applying test pulses to different pairs of theelectrodes and measuring at least one electrical characteristic of thestenosis cells for the different pairs of electrodes.

In another aspect of the invention, the step of determining includesmeasuring an electrical resistance as the at least one electricalcharacteristic of tissue cells.

In another aspect of the invention, the method further comprisesdisplaying a graphical representation and identification of theelectrodes in positional relationship to the stenosis. In other words,electrode numbers are shown in relation to the position of the lesion soas to enable a user to determine which electrodes are the closest to thelesion and which electrodes close to the deepest part of the lesion.

In another aspect of the invention, the method further comprisesdisplaying a graphical representation of the stenosis and a graphicalrepresentation and identification of the electrodes in positionalrelationship to the stenosis.

In another aspect of the invention, the method comprises electroplatingtissue for the purpose of facilitating electrochemotherapy orelectrogenetherapy, wherein cells are reversibly electroporated insteadof killed, or the treatment is administered without necessarily killingcells or target tissue. Such methods can include inserting into a vesselan electrode having a plurality of elongated electrically conductivewires disposed lengthwise along the electrode and circumferentiallyspaced a selected distance from one another; orienting the electrodewithin the vessel to provide one or more of the electrically conductivewires in position to deliver one or more electrical pulse to targettissue; selecting one or more but less than all of the electricallyconductive wires for administering the electrical pulse(s);administering the electrical pulse(s) from the selected electricallyconductive wires to deliver the electrical pulse(s) to the target tissueand less than all vessel circumference; and wherein the administering isperformed for a time and under circumstances sufficient to deliver drugsor genes to the target tissue or a portion thereof.

Such electrodes can also be used to enable directional targeting forother electroporation based therapies as well. For example, methods ofdirectional targeting for selective macromolecule delivery, such as genetransfer are another application for electrodes of the invention. Moreparticularly, the electrodes can be used for delivering insulin-makinggenes to pancreatic islets by way of the splenic artery; or can be usedin chemotherapy treatments, especially for tumors; or can be used forother improved drug uptakes, such as for non-cancerous drug transportsas well. Indeed, devices of the invention can be used as a device fordirectionally delivering any number of electrically-relevantinterventional procedures to be delivered in a radially directed mannerthrough blood vessels. Yet other applications include directionalradiofrequency ablation or deep-brain stimulation, to name a couple.

According to another embodiment of the present invention, a medicaldevice for treating a stenosis of a tubular body part by non-thermalirreversible electroporation is provided. The device includes a pulsegenerator, a balloon catheter, and at least three individuallyaddressable (electrically independent) electrodes. The pulse generatorgenerates electrical pulses in an amount which is sufficient to induceirreversible electroporation of cells of a stenosis to be treated, butwhich is insufficient to induce thermal damage to substantially all ofthe cells of the stenosis. The electrodes are positioned and spacedapart along the balloon, and electrically independent from each other.The electrodes are adapted to receive the electrical pulses from thepulse generator such that substantially all of the cells of the stenosisare killed by non-thermal irreversible electroporation. The ability toselect which electrodes to energize based on the proximity of the lesionto the electrodes allows more precise targeting of the lesion whileminimizing possible damage to surrounding healthy tissue.

In another aspect of the invention, the medical device further comprisesa switch connected between a pulse generator and the electrodes, andadapted to connect the pulse generator output to any pair of theelectrodes independent of the other electrodes.

In another aspect of the invention, the medical device further comprisesa treatment control module adapted to control the switch to output theelectrical pulses to those electrodes that have been selected based on adetermination of which electrodes are near the stenosis.

In another aspect of the invention, the treatment control module isadapted to determine at least one individualized electrical parameterfor each pair of electrodes based on a determination of which electrodesare near the stenosis.

In another aspect of the invention, the electrical parameter of thetreatment control module includes Voltage or pulse duration.

In another aspect of the invention, the medical device further comprisesone or more imaging markers disposed near the electrodes to determinewhich electrodes are near the stenosis.

In another aspect of the invention, the medical device comprises imagingmarkers that include a radiopaque marker.

In another aspect of the invention, the treatment control module isadapted to determine which electrodes are near the stenosis by applyingtest pulses to different pairs of the electrodes and measuring at leastone electrical characteristic of the stenosis cells for the differentpairs of electrodes.

In another aspect of the invention, the treatment control module isadapted to measure an electrical resistance as the at least oneelectrical characteristic of tissue cells.

In another aspect of the invention, the treatment control module isadapted to display a graphical representation and identification of theelectrodes in positional relationship to the stenosis.

In another aspect of the invention, the treatment control module isadapted to display a graphical representation of the stenosis and agraphical representation and identification of the electrodes inpositional relationship to the stenosis.

In another aspect of the invention, the treatment control module isadapted to determine at last one individualized electrical parameter foreach pair of electrodes based on the depth and proximity of the stenosisin relation to the electrode positions.

In another aspect of the invention, the treatment control module isadapted to determine an individualized voltage level to use for eachpair of electrodes based on the depth of the restenosis near the eachpair.

In another embodiment of the invention, a method for treating a lesionof a tubular body part by non-thermal irreversible electroporation isprovided. The method includes: (a) inserting into the tubular body parta plurality of elongated electrodes disposed lengthwise andcircumferentially spaced a selected distance from one another; (b)positioning the electrodes within the tubular body part to provide oneor more of the electrodes in position to deliver a plurality ofelectrical pulse to a target lesion; (c) selecting electrodes among theplurality of electrodes for administering the electrical pulses; and (d)administering the electrical pulses through only the selected electrodesto the target lesion in an amount which is sufficient to induceirreversible electroporation of cells of the target lesion, but which isinsufficient to induce thermal damage to substantially all of the cellsof the target lesion such that substantially all cells of the targetlesion are killed by non-thermal irreversible electroporation.

In another aspect of the invention, the electrode comprises a flexiblecatheter and inflatable balloon and the electrodes are disposedlengthwise along and are circumferentially spaced around a surface ofthe inflatable balloon.

In another aspect of the invention, the method further comprisesdetermining an orientation of the electrode within the tubular body partby imaging, wherein the electrode comprises at least one imaging markerfor determining location of the electrodes.

In another aspect of the invention, the method further comprisesmeasuring a distance between the imaging markers and using the distancesto calculate rotational orientation of the electrode.

In another aspect of the invention, the one marker is radio-opaque.

In another aspect of the invention, at least two radio-opaque markersand at least one intravascular ultrasound marker are provided on or nearan inflatable balloon.

In another aspect of the invention, the selection step includes: (a)administering one or more test pulses through any one or more of pairsof the electrodes; (b) determining from the test pulses one or moreelectrical characteristics of tissue subjected to the test pulses andbased on the electrical characteristics further determining a depth ofthe target lesion; and (c) generating a protocol for administeringhigher voltage electrical pulses between electrode pairs positioned fortreating deep restenosis and for administering lower voltage electricalpulses between electrode pairs positioned for treating shallowrestenosis.

In another aspect of the invention, the test pulse or signal is anon-electroporating test pulse.

Additionally, in embodiments having an inflatable balloon, theelectrically conductive wires (electrodes) can be disposed lengthwisealong the electrode and can be circumferentially spaced around theelectrode. In preferred embodiments, the electrically conductive wiresare disposed circumferentially around the electrode and in contact witha surface of the inflatable balloon.

According to methods of the invention, orientation of the electrodewithin a body or vessel can be determined. This is particularly helpfulfor example in situations where it is desired to treat only a portion ofthe circumferential surface area of a blood vessel. In this situation,it may be desired to know the location of fewer than all of theelectrically conductive wires relative to the location of asymmetricalrestenosis within a blood vessel. Knowing the relative location of thewires, a practitioner can selectively energize only that portion of theelectrode to treat the restenosis site thus leaving intact healthytissue remaining on other portions of the circumferential surface areaof the blood vessel. One such technique can employ an electrodecomprising at least one imaging marker and determining the location ofthe electrically conductive wires by imaging the device in a body orvessel.

Using techniques of the invention and an electrode with at least oneimaging marker, methods of the invention can include measuring adistance between the imaging markers and using the distances tocalculate rotational orientation of the electrode.

Imaging markers disposed in the electrodes of the invention can beradio-opaque. In embodiments, electrodes can comprise at least oneradio-opaque marker. In preferred embodiments, the electrodes cancomprise at least two radio-opaque markers and at least oneintravascular ultrasound marker. Further, there can be a plurality ofradio-opaque markers, each associated with an individual electricallyconductive wire of the electrode.

Another method for determining orientation relative to stenotic tissueof electrically conductive wires of an electrode can comprise: (a)inserting into a treatment area, such as a vessel, an electrode having aplurality of electrically conductive wires; (b) administering one ormore test signals between two of the electrically conductive wires andsubjecting tissue to the test signal(s); (c) determining from the testsignal(s) one or more electrical characteristics of the tissue subjectedto the test signal(s); and (d) comparing the electricalcharacteristic(s) to one or more threshold to confirm whether the tissuesubjected to the test signal(s) is stenotic and whether the electricallyconductive wires are in position to deliver an electrical charge totarget stenotic tissue.

The electrical characteristics of the tissue can be determined, e.g.,from resistance measurements, impedance measurements, and electricalimpedance tomography.

Further embodiments of the invention include a method of mapping depthof stenotic tissue in real-time comprising: (a) inserting into a vesselan electrode having pairs of electrically conductive wires; (b)administering one or more test pulse between any one or more, or all, ofthe electrically conductive wire pairs; (c) determining from the testpulse(s) one or more electrical characteristics of tissue subjected tothe test pulse(s) and based on the electrical characteristics furtherdetermining depth of stenosis; and (d) generating a protocol foradministering higher voltage electrical pulse(s) between electricallyconductive wire pairs positioned for treating deep stenosis and foradministering lower voltage electrical pulse(s) between electricallyconductive wire pairs positioned for treating shallow stenosis.

Methods disclosed in this specification can be used for treating,preventing, and/or reducing stenosis. Thus, methods according toembodiments of the invention may include identifying stenotic tissue asthe target tissue.

An irreversible electroporation medical device is also encompassedwithin the scope of the present invention and can comprise: (a) anintravascular catheter type electrode having an inflatable balloon and aplurality of electrically conductive wires disposed lengthwise along theelectrode/balloon/catheter; and (b) a plurality of imaging markers, eachdisposed relative to an electrically conductive wire, such that themarkers, when subjected to imaging, reveal the identification of eachwire and the distance between markers from which rotational orientationof the electrode within a body can be determined. In embodiments, theelectrically conductive wires can be elongated and circumferentiallyspaced around the electrode a selected distance from one another. Inother embodiments, the electrically conductive wires can be annular andlongitudinally spaced along the length of the electrode a selecteddistance from one another.

Such methods can employ devices comprising imaging markers that areradio-opaque. Preferably, methods can comprise an electrode with atleast two radio-opaque markers and at least one intravascular ultrasoundmarker to be used in determining orientation of the electrode relativeto a treatment site.

Systems are also included within the scope of the invention. Suchsystems can include an intravascular IRE system comprising: (a) at leastone intravascular catheter type electrode having an inflatable balloonand a plurality of electrically conductive wires disposed lengthwisealong the electrode and circumferentially spaced a selected distancefrom one another; (b) an electrical pulse generator in operablecommunication with and for delivering electrical pulses to the pluralityof electrically conductive wires; and (c) a control system in operablecommunication with the electrical pulse generator comprising a computerprogram embodied in a computer-readable storage medium, which programwhen executed, enables a computer to perform a method comprising: (i)determining orientation of the electrically conductive wires relative totarget tissue; (ii) selecting one or more but less than all of theelectrically conductive wires for administering the electrical pulse(s);and (iii) energizing one or more of the electrically conductive wires todeliver the electrical pulse(s) to the target tissue.

Objects of the invention include computer programs for running the IREmethods, systems, and devices described in this specification. Suchcomputer programs can be embodied in a computer-readable storage medium,which when executed, enables a computer to perform a method comprising:(a) determining orientation relative to target tissue of at least oneelectrically conductive wire of an electrode; (b) selecting one or morebut less than all of the electrically conductive wires for administeringelectrical pulse(s); and (c) energizing the selected wires to deliverthe electrical pulse(s) to the target tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate certain aspects of some embodimentsof the present invention, and should not be used to limit or define theinvention. Together with the written description the drawings serve toexplain certain principles of the invention.

FIGS. 1A-B are schematic diagrams showing a representative embodiment ofa catheter type electrode device according to the present invention,where FIG. 1A shows all components clear to see underlying structure andwhere FIG. 1B shows the labeled components with opaque inner components.

FIG. 1C is a schematic diagram representing the different layers anddimensions used in various numerical simulations of IRE in the coronaryartery, in which (described from the innermost region to the outermostregion) a catheter with electrodes, blood, plaque, and smooth musclewere modeled.

FIG. 1D is a schematic diagram of an electrode of the inventioncomprising a catheter type device with embedded electrodes at alongitudinal separation distance of 5 mm.

FIG. 1E is a schematic diagram illustrating an electrode embodiment ofthe invention which is a catheter type device with embedded electrodesthat can be used for IRE treatment of neointimal hyperplasia.

FIGS. 2A-B are schematic diagrams showing a cross-sectional view of anumerical model setup for symmetric restenosis (FIG. 2A) and asymmetricrestenosis (FIG. 2B).

FIGS. 3A-D are schematic drawings illustrating a cross-sectional view ofa representative numerical model output of electric field following a100 μs pulse at 400 V, and more particularly: for treating symmetricrestenosis with all 8 wires energized (FIG. 3A); for treating symmetricrestenosis with 2 wires energized (FIG. 3B); for treating asymmetricrestenosis with all 8 wires energized (FIG. 3C); and for treatingasymmetric restenosis with 2 wires energized (FIG. 3D).

FIGS. 3E-F are schematic drawings illustrating a cross-sectional view ofa representative numerical model output of temperature following a 100μs pulse at 400 V, and more particularly: for treating symmetricrestenosis with all 8 wires energized (FIG. 3E) and with only 2 wiresenergized (FIG. 3F).

FIG. 4 is a flowchart illustrating a method of selectively energizingone or more electrically conductive wires of an electrode for treatingtarget tissue.

FIG. 5 is a schematic diagram of a representative electrical circuit foran electrode system of the invention, which circuit enables selectiveelectrode energizing.

FIG. 6A is a schematic diagram of a balloon type catheter electrodecomprising a plurality of electrically conductive wires disposedlongitudinally over the length of the balloon.

FIG. 6B is a schematic diagram showing a cross-sectional view of theelectrode illustrated in FIG. 6A comprising a radio-opaque markerdisposed proximate each wire.

FIG. 6C is a schematic diagram illustrating markers disposed on aballoon type catheter electrode which would appear on an imagingapparatus, such as ultrasound, CT or X-ray, foridentification/determination of the electrically conductive wires on theelectrode.

FIGS. 6D-G are schematic diagrams illustrating orientation of themarkers comprised in a balloon type electrode, which is shown at variousorientations within a body.

FIG. 6H is a schematic diagram showing the cross section and a side viewof a representative electrode with imaging markers to indicate electrodeorientation.

FIGS. 6I-M are schematic diagrams showing a top view of the electrode ina blood vessel, illustrating how the imaging markers would show up on animaging apparatus when oriented in various rotational orientationswithin the vessel.

FIG. 7 is a schematic diagram illustrating an IRE system of theinvention.

FIG. 8 is a schematic diagram illustrating a control system forimplementing methods of the invention and/or operating systems anddevices of the invention.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS OF THE INVENTION

Reference will now be made in detail to various exemplary embodiments ofthe invention. It is to be understood that the following discussion ofexemplary embodiments is not intended as a limitation on the invention.Rather, the following discussion is provided to give the reader a moredetailed understanding of certain aspects and features of the invention.

Embodiments of the present invention include devices, systems, andmethods employing expandable radially targeting electrodes. Theelectrodes can be designed for endovascular-based electroporationtherapies and adapted for implementation with catheter-based guidance.This type of electrode with independently energized surfaces is alsoadaptable to any number of physical and clinical scenarios where radialtargeting is desired.

Preferred electrode designs can be configured to use the combination ofelectrically conductive wires with an angioplasty balloon to bring theelectrodes into direct contact with the targeted region, such asneointimal tissue. More specifically, designs of the present inventioncan employ for example eight independent conducting surfaces (wires orhighly conducting solutions) to administer the electric pulses. The useof multiple conducting surfaces contained within the same electrodepresents many advantages over the current state of the art designs. Theelectrically conductive surfaces of the electrode are not limited towires. For example, any structure capable of providing a surface fordelivering an electric charge can be used, including where theelectrically conductive surfaces are bands or strips of material, or areprinted on the surface of the balloon, or even further are compartmentswithin an inflatable balloon comprising a highly conductive solution.Energizing the electrically conductive surfaces in sequence rather thancollectively promotes an outward distribution of the electric field,reducing thermal effects and requiring lower voltages for treatment.Such techniques provide for an expanded treatment zone by energizingonly a few of the electrically conductive wires at a time rather thanthe entire circumference of the electrode in one shot. In addition, byallowing independent spatial control of which portions of the electrodeare energized (i.e., which wires), the electric field distribution maybe customized in a manner that most effectively treats a specificlesion, such as an asymmetrical restenosis, while minimizing anydamaging effects on healthy tissue. This allows a practitioner to moreaggressively treat focally enlarged portions of a lesion while beingmore conservative on smaller regions of the same stenosis, which isimportant because it allows for improved accuracy in restenosis-ablationvascular-based surgeries. Further, applications include targeting othervolumes located only on one side of a vessel, such as gene transfertargets just outside the vessel or tumor ablation using the tumorvasculature.

Accordingly, embodiments of this invention may be used as acatheter-style electrode to access target restenotic lesions from withinthe vessel. Embodiments of the present invention may also be used totarget tissue disposed outside of the outer circumference of a vessel,such as an area between two or more blood vessels within a body. The useof a catheter electrode allows a practitioner to insert the electrodethrough a peripheral vessel, as is typical of current percutaneousvascular techniques, such as angioplasty and stenting. This renderstreatments minimally invasive and advantageous over previous IREinvestigations on blood vessels.

In the context of this specification, it should be noted that the terms“electrode,” “electrode device,” “device,” “balloon catheter electrode,”“catheter electrode,” or “device” are typically used to refer to the IREmedical device as a whole, which may include a catheter, balloon, andelectrically conductive wires. The terms “conducting surfaces,”“electrically conductive wires,” “conducting wires,” “wire electrodes,”and “wires” are typically used to refer to a portion of the electrode,such as a pair or pairs of electrodes, which may be selectivelyenergized to deliver electrical pulses. Notwithstanding these typicalmeanings, in some embodiments in this specification, the terms may beused interchangeably.

Exemplary electrodes according to embodiments of the invention are shownin FIGS. 1A-E. More particularly, as shown in FIGS. 1A-B, some of thecomponents of the electrode device include a guidewire, tip, outer body,connector, balloon, and partially insulated conducting wires. Theconfiguration depicted in this embodiment has a 2 mm diameter and istherefore designed for larger coronary vessels, such as the rightcoronary artery or left main artery, with proximal to medial lumendiameters of roughly 3.6 and 4.3 mm, respectively. See Dodge, J. T.,Jr., B. G. Brown, E. L. Bolson, and H. T. Dodge, Lumen diameter ofnormal human coronary arteries, Influence of age, sex, anatomicvariation, and left ventricular hypertrophy or dilation, Circulation,1992, 86(1): p. 232-46. Such vessels may have typical restenotic lumendiameters of approximately 2.5 mm. See Radke, P. W., A. Kaiser, C.Frost, and U. Sigwart, Outcome after treatment of coronary in-stentrestenosis—Results from a systematic review using meta-analysistechniques, European Heart Journal, 2003, 24(3): p. 266-273.

Modern micromachining techniques will allow for the construction of evensmaller designs that may target smaller vessels, such as the distalportions and branches of the coronary arteries. Indeed, the devices ofthe present invention may also be scaled up for other applications.Accordingly, the diameter of the outer body of electrodes of theinvention can range for example from about 0.1 mm up to about 5 cm.Preferably, electrode embodiments of the invention have an outerdiameter ranging from about 0.5 mm to 5 mm, such as from about 1 mm toabout 3 mm, such as about 1.5 mm to about 2 mm, or from about 0.75 mm to3 cm.

In embodiments, the guidewire is the narrowest physical component and isused to direct the surgeon into the appropriate vessel. Although nottypical, it can be hollow so that it may be used with a soluble contrastagent used for angiography and fluoroscopy, similar to typicalendovascular therapies. See Schwartz, R. S., J. G. Murphy, W. D.Edwards, A. R. Camrud, R. E. Vliestra, and D. R. Holmes, Restenosisafter balloon angioplasty, A practical proliferative model in porcinecoronary arteries, Circulation, 1990, 82(6): p. 2190-200. The guidewireis usually of a smaller diameter than the diameter of the outer body ofthe balloon.

The guidewire or catheter forms the support for which all othercomponents of the device are arranged. Over a portion of the catheterbetween the distal tip and the proximal end of the device is disposed aninflatable balloon. The balloon is secured to the catheter at the distaland proximal ends of the device. An inflation mechanism for providing afluid into the area between the balloon and catheter is also provided.The balloon can be inflated during use with any inert fluid, such assaline, contrast fluid, air, or even low electrical conductivity sucrosesolution. In embodiments where the electrically conductive wires aredisposed on the inside of the balloon (between the balloon and thecatheter) and where there is present a highly conductive fluid in thelumen (inside the balloon), the flow of the current would bepreferentially through the fluid rather than through the wires which mayresult in a more diffuse electrical field. In preferred embodiments, alow-conductivity buffer is preferred as the fluid to inflate the balloonto more accurately treat target tissue.

The partially insulated conductive wires or electrodes provide fordelivering the IRE electrical charge to target tissue from an electricalpulse generator. During use of the device, proximal ends of thewires/electrodes are in operable communication with a pulse generator.The wires can be hardwired directly to the pulse generator, or inpreferred embodiments the electrode is equipped with a universalconnector (or other connecting structure) for securing the electricallyconductive wires/electrodes to the electrical pulse generator in anoperably connective manner. For electrodes having a greater number ofelectrically conductive wires than the number of outputs available on apulse generator it is desired to be used with, the electrodes and orpulse generator can be retrofitted or adapted accordingly to operablycooperate with one another. In embodiments, when there are moreconductive wires on the electrode, e.g., 8 wires, than there are outputson the pulse generator, e.g., 6 outputs, systems of the invention cancomprise an electrode-generator interface that cooperates with thegenerator to switch which wires are active for a given pulse set in theoverall sequence. More specifically, the interface can comprise a switchfor switching between wires 4 and 8 for an 8-electrode system, sincethose wires would be least likely to be energized at the same time at180° apart. Other examples for operation of an interface for treatmentsusing basic 2-at-a-time pulsing pairs, the system can be connected toall 8 wires on the output, and just have a positive and negative inputto take from the generator, where it would automatically switch pairs1-2 to 2-3 and so on, while the generator's positive and negativeoutputs (port 1 and 2) would change pulse set 1 at (ex.) 2000 V (wires1-2), then change to 1500 V (wires 2-3) for the second.

In this embodiment, the electrically conductive wires are elongated andare disposed along the length of the balloon. The wires are spaced aselected distance from one another around the circumference of theelectrode. In FIGS. 1A-B, there are eight electrically conductivewires/electrodes circumferentially spaced around the balloon. The distalends and proximal ends of the electrically conductive wires/electrodesare protected or encased by an outer insulative body, while a medialportion of the wires/electrodes is exposed to the atmosphere or vesselwall when implanted.

The distal tip of the balloon preferably includes a conical distal endto allow easy advancement through the vessel lumen. The conical distalend is preferably formed from or is in operable communication with aportion of the outer body of the device. The outer body of the device isan insulative encasing providing protection for the components of thedevice and for controlling the amount of exposure of the electricallyconductive wires. Another portion of the outer body of the deviceprovides for a proximal encasing disposed at the proximal end of theelectrode. In embodiments, there is a gap or separation distance betweenthe distal and proximal encasings or portions of the outer body. Thisgap or unprotected area of the electrode exposes the electricallyconductive wires to the atmosphere.

A connector is disposed proximally of the balloon. The connector ishollow to allow movement with respect to the guidewire, and has aninternal chamber that extends all the way back to the proximal ends ofthe balloon catheter that can carry fluids, such as physiologic salineor air or low electrical conductivity sucrose solution.

The balloon is attached to the connector. Running through thebody/connector assembly is an array of 8 conducting 35 gauge wires (0.15mm). These wires are insulated throughout the electrode apparatus untilthey reach the highly insulative balloon, after which they are exposed.In embodiments, the conducting wires can be attached to the proximalportion of the connector, but their distal ends are free and enclosedwithin the casing of the tip. This allows free expansion of the wireswith inflation of the balloon. In other embodiments, the wires can beattached to the surface of the balloon and/or the distal ends of thewires attached to the distal tip, or distal outer body, or distalportion of the connector of the electrode. One example of an electrodeballoon catheter is disclosed in U.S. patent application Ser. No.12/413,332 filed Mar. 27, 2009 and entitled “IrreversibleElectroporation Device And Method For Attenuating Neointimal”, which isincorporated herein by reference.

During use with the electrode inserted into a blood vessel, when theballoon is inflated with a fluid, the electrodes (electricallyconductive wires) are expanded, and placed into contact with thetargeted neointimal tissue disposed within the inner circumference ofthe blood vessel. In the embodiment shown, the length of exposure ofeach electrode is about 5 mm. However, larger exposure lengths may beused to treat diffuse restenosis lesions. See Rajagopal, V. and S. G.Rockson, Coronary restenosis: a review of mechanisms and management, TheAmerican Journal of Medicine, 2003, 115(7): p. 547-553. In specificembodiments, the exposure length of the electrically conductive wiresand thus the exposed portion of the electrode can range from about 0.1mm to about 5 cm, such as from about 0.5 mm to about 3 cm, or from about0.8 mm to about 2 cm, or from about 1 mm to about 1 cm, or from about1.5 mm to about 0.5 cm, or from about 2 mm to about 10 mm, or from about2.5 mm to about 7 mm, or from about 3 mm to about 6 mm, such as fromabout 3.5 mm to about 4 mm, etc.

FIGS. 1C-D provide another device embodiment of the invention. In thisembodiment, the electrodes can comprise electrically conductive wiresthat are longitudinally spaced a selected distance from one anotheralong the circumference of the balloon. As shown in FIG. 1C, anelectrode of about 1 mm in diameter can be inserted lengthwise into ablood vessel. For illustration purposes, the blood vessel here has anouter diameter of about 20 mm and, when healthy, an inner diameter ofabout 4 mm. As illustrated in this case here, however, there is plaquebuild up, stenosis, or restenosis in the blood vessel, leaving onlyabout a 2 mm inner diameter for the flow of blood through the vessel. Asshown, an IRE device according to the invention is inserted into theblood vessel and used to ablate all or a portion of the growth withinthe vessel that is obstructing blood flow. In embodiments, there can bemultiple rings (instead of 2) spaced along the longitudinal length ofthe electrode, and the applied voltages between each ring-pair (2conductive regions energized) or ring-set (>2 conductive regionsenergized at a time). Preferably, the IRE device is orientedrotationally within the blood vessel to deliver one or more electricalcharge(s) to target tissue disposed only around a portion of the innercircumference of the blood vessel. To further illustrate placement ofthe electrode within a blood vessel, FIG. 1D provides a perspective viewof an electrode device embodiment of the invention inserted lengthwiseinto a blood vessel with the electrically conductive wires disposedproximate target tissue.

FIG. 1E provides a representative example of another electrodeconfiguration according to embodiments of the invention. Examples ofother configurations that can be used are disclosed in US PublishedPatent Application No. 2010/0030211, filed Jun. 24, 2009; US PublishedPatent Application No. 2001/0044596, filed May 4, 2001; and US PublishedApplication No. 2009/0247933, filed Mar. 27, 2009.

The device 700 illustrated here in FIG. 1E, provides a minimallyinvasive microsurgical tool that uses IRE in coronary arteries to treatneointimal hyperplasia. Generally, the electrode 700 is a catheter typedevice with embedded active 712 and ground 711 electrically conductivewires. The electrically conductive wires 711, 712 are annular in shapeand are disposed lengthwise along the length of the distal tip 710 ofthe electrode 700. The conductive wires 711, 712 are spaced a selecteddistance from one another longitudinally along the length of theelectrode 700 and are separated by sections of insulation. The electrode700 is compatible with existing electroporation electronics andcomprises a universal connector 750 for connecting the proximal end 718of the electrode 700 in operable communication with an electrical pulsegenerator. Existing systems that can be used and/or adapted for use withdevices and methods of the invention include the NanoKnife® system fromAngioDynamics® of Latham, N.Y. A portion of the electrically conductivewires 711, 712 is encased within the outer body 770 of electrode 700, orelectrically conductive leads run from the electrically conductive wires711, 712 along the length of the electrode 700 from the distal tip 710to the proximal end 718 for operable communication with an electricalpulse generator.

The electrically conductive wires can comprise any type of conductingmetal, such as platinum/iridium. Different materials will have differentradio-opacity and can be selected according to this characteristic toachieve a particular result. For example, silver is much moreradio-opaque than titanium and thus some embodiments of electrodes ofthe invention can have titanium conductive surfaces/wires, while usingsilver for the markers. To ensure biocompatibility, embodiments of theelectrode can be sheathed with an insulating polyurethane jacket 770 toenclose the electrically conductive wires leading to the electricalpulse generator. In embodiments, the electrical conducting wires do notneed to be entirely conducting. For example, the electrical conductivesurfaces can comprise a portion or portions with an insulating coating(especially near their base). The exposed portions or surfaces of theelectrically conductive wires 711, 712 on the distal tip 710 can be anythickness and width. Likewise, the amount of separation distance betweenthe electrically conductive wires at the distal tip 710 can be anyamount, and the electrodes can comprise any number of conductive wires.In embodiments, the electrodes can be configured in a manner to providefor an adjustable separation distance between electrically conductivewires, and/or an adjustable amount of exposed conductive surface.

This embodiment is constructed as a thin device, which allows for easynavigation through the cardiovascular system directly into the treatmentsite. In embodiments where there is no guidance catheter placed first(as in FIG. 1E), the electrode can comprise a J-shaped tip (or similarshape) as is common in angioplasty and catheter-based interventions soas to enable guidance of the electrode through the vasculature to reachthe target site. Such an asymmetric tip could also be used as a sourcefor determining rotational orientation for this particular embodiment.The electrically conductive wires, separated by an insulating material,generate the electric field distribution that determines the IRE treatedregions. Representative dimensions of the electrode device, such asabout 0.5 mm in diameter, ensures that it is feasible to be placed inthe coronary artery since it is smaller than those already used incatheterization. The diameter or width is thus on the order of 0.5 mm to1 cm. Preferably, the diameter or width is about 0.5 mm to about 5 mm,such as about 1 mm, 2 mm, 3 mm, or 4 mm. The length of the device is notparticularly limited, but is generally set such that a surgeon can usethe device comfortably to treat lesions at any position in the body.Thus, for human use, the device is typically on the order of 40 cm orless in length, such as about 30 cm, 25 cm, or 15 cm, whereas forveterinary use, the length can be much larger, depending on the size ofanimal to be treated. For treatment of human brain tumors, the lengthcan be on the order of 40 cm.

The device can be customized by varying the diameters and separationdistances of the electrically conductive wires, thus unique IRE treatedareas can be predicted using mathematical models. As a result,successful treatment for neointimal hyperplasia is ensured due to theability to match different plaque sizes and shapes.

Further, in some embodiments, the IRE device, or a portion thereof, isflexible. A flexible device is advantageous for use in accessing lesionsnon-invasively or minimally invasively through natural body cavities. Inembodiments where the device or a portion of it is flexible, the shapeof the device can change based on contact with body tissues, can bepre-set, or can be altered in real-time through use of wires or othercontrol elements, as known in the art, for example in use withlaparoscopic instruments.

Smooth muscle cells are the primary component of the neointimalhyperplasia typical of in-stent restenosis. See Rajagopal, V. and S. G.Rockson, Coronary restenosis: a review of mechanisms and management, TheAmerican Journal of Medicine, 2003, 115(7): p. 547-553. In order to killthese cells without damaging the healthy vessel architecture, it isdesirable to harness the non-thermal mechanism of IRE to kill cellswithout inducing thermal damage. Mitigating thermal damage allows theextracellular matrix, nerves, and other sensitive structures to bespared. This allows for healthy regrowth of the tissue.

The primary factor determining the effect of an electroporationprocedure is the electric field to which the tissue is exposed. However,IRE protocols have a variety of electrical pulse parameters that mayalso affect the toxicity of the treatment. In addition to the electricfield, these include pulse shape, number of pulses, pulse length, andrepetition rate. The thermal effects of an IRE treatment during a pulseare a direct function of the conductivity of the tissue and the voltageto which it is exposed. Therefore, minimizing the thermal effects for aparticular tissue type may be done by finding the minimum requiredelectric field, and thus applied voltage, to kill the cells in thetissue.

To this end, pulsing parameters and electrode configurations accordingto embodiments of the invention can include any combination of any ofthe following: a pulse length in the range of about 1 μs to 1 ms; anumber of pulses ranging from 1 to 10,000; an electric fielddistribution for each conductive wire pair and/or across a treatmentregion ranging from about 5-5,000 V/cm; a total electrical chargedelivered by way of each conductive wire pair and/or across a treatmentregion of about 0.1 to about 500 mC; a frequency of pulse applicationranging from about 0.001-100 Hz; a frequency of pulse signal rangingfrom about 0-100 MHz; a pulse shape that is square, exponential decay,sawtooth, sinusoidal, or of alternating polarity although the currentlyfavored pulse shape is a biphasic DC pulse; a positive, negative, andneutral electrical charge pulses (changing polarity within the pulse); aresulting current in the treated tissue ranging from about 0 to about100 amps; from 1-20 electrodes and/or electrically conductive wires; anelectrode and/or electrically conductive wire separation distanceranging from about 0.1 mm to about 5 cm; and multiple sets ofpulse/electrode parameters for a single treatment, including changingany of the above parameters within the same treatment, such as removingthe electrodes and replacing them in different locations within thetissue or changing the number of electrodes, to specialize/customizeoutcome.

For example, in embodiments a pulse length in the range of about 1 μs to1 ms, such as from about 5 μs to about 0.5 ms, or from about 10 μs toabout 0.1 ms, or from about 15 μs to about 95 μs. Pulse lengths of 20μs, 25 μs, 30 μs, 35 μs, 40 μs, 45 μs, 50 μs, 55 μs, 60 μs, 65 μs, 70μs, 75 μs, 80 μs, 85 μs, 90 μs, 110 μs, 150 μs, or 200 μs, and so on arealso acceptable. The number of pulses can range for example from 5 to5,000, or from about 10 to 2,000, or from about 20 to 1,000, or fromabout 30 to 500, or from about 50 to 200, or from about 75 to 150, orfrom about 90 to 120, or from about 95 to 110, or about 100 pulses.

Typically, the electric field distribution for each conductive wire pairand/or across a treatment region for IRE is performed using voltagesranging for example between 1500 V/cm to 4,000 V/cm. Voltages of muchlower power can also be used, including using less than about 1500 V/cm.Applied fields of about 500 V/cm to 1000 V/cm can be used, or even ofabout 10 V/cm to about 750 V/cm, such as from about 50 V/cm to about 200V/cm, or an electric field distribution of about 75 V/cm to about 100V/cm. For example, in the treatment of brain tumors, typically, anapplied field of less than 1000 V/cm can be used. Electrical pulsegenerators that can be used include those capable of delivering from 0to about 5,000 V, such as the NanoKnife® system of AngioDynamics®, whichfor example can deliver from 0-3,000 V.

In preferred embodiments, a total electrical charge delivered by way ofeach conductive wire pair and/or across a treatment region of about 0.5to about 25 mC can be used, such as about 1 mC to about 20 mC, or fromabout 1.5 mC to about 15 mC, or from about 2 mC to about 10 mC, or fromabout 5 mC to about 8 mC, and so on. Similarly, in preferredembodiments, the resulting current in the treated tissue can range forexample from about 1 A to about 8 A, or from about 2 A to about 6 A, orfrom about 3 A to about 5 A, such as 4 A. Indeed, for certainapplications the total electrical charge delivered can range from about0.5 to about 500 mC, such as about 10 mC to about 200 mC, or from about15 mC to about 150 mC, or from about 20 mC to about 100 mC, or fromabout 50 mC to about 80 mC, and so on. The resulting current in thetreated tissue can range for example from about 1 A to about 80 A, orfrom about 20 A to about 60 A, or from about 30 A to about 50 A, such as40 A. It is not uncommon for currents for IRE treatments to reach orexceed 40 and 50 amps, and it is further feasible to operate under evenhigher current with pulse generators capable of operating under suchconditions as well. Currents are expected to be high in certainapplications, especially when working in an area where the tissue or themedium is highly conductive, such as with blood present in a bloodvessel. Pulse width, pulse shape, number of pulses, and the resultantcurrent in the tissue can be adjusted to achieve specific target goalsfor limiting the total electric charge, and any of the specific valuesdisclosed in this specification can be used to calculate the targetexpected charge.

Any number of electrically conductive wires or electrodes can also beused. However, in preferred embodiments 3 to about 18 electrodes areused, such as 3 to 16, or from about 3 to 15, or from 4 to 12, or from 5to 10, or from 6 to 8. Any one or more of the electrodes/wires can beselectively energized to achieve a particular treatment result. Further,the separation distance between electrically conductive surfaces, suchas electrically conductive wires and/or electrodes, can range from about0.2 mm to about 4 mm, such as ranging from about 0.3 mm to about 3 mm,or from about 0.4 mm to about 2 mm, or from about 0.5 mm to about 1 mm,or from about 0.8 mm to about 4 cm, such as from about 0.9 mm to about 3cm, or from about 1.2 cm to about 2 cm, or from about 1.5 cm to about1.8 cm, and so on.

The electric field needed for a particular situation may be predictedthrough numerical modeling, allowing for reliable treatment planning.See Davalos, R. V., L. M. Mir, and B. Rubinsky, Tissue Ablation withIrreversible Electroporation, Ann Biomed Eng, 2005, 33(2): p. 223-231;Robert E. Neal I I and R. V. Davalos, The Feasibility of IrreversibleElectroporation for the Treatment of Breast Cancer and OtherHeterogeneous Systems, Ann Biomed Eng, 2009, 37(12): p. 2615-2625; andEdd, J. F. and R. V. Davalos, Mathematical Modeling of IrreversibleElectroporation for Treatment Planning, Technol Cancer Res Treat, 2007,6(4): p. 275-286. To determine the efficacy of the electrode andunderstand the effects of the pulses on tissue, a numerical model hasbeen developed capable of simulating treatments. This was done using afinite element software package, COMSOL Multiphysics (COMSOL, Stockholm,Sweden).

Two representative models were developed, simulating the cross sectionof a typical artery with a symmetric or an asymmetric restenosis. Themodel setups for the electrodes of FIGS. 1A-B are illustrated in FIGS.2A-B.

In the numerical models illustrated, both use a blood vessel outerdiameter of about 3.6 mm, with a combined tunica media and adventitiathickness of 200 μm, which are representative values derived from visualinspection of results from Maor, E., A. Ivorra, J. Leor, and B.Rubinsky, The Effect of Irreversible Electroporation on Blood Vessels,Technol Cancer Res Treat, 2007, 6(4): p. 307-312. These vessel layersare considered to be composed of collagen and elastin, as described inSaladin, K. S., The Circulatory System III—Blood Vessels, in HumanAnatomy. 2008, Mcgraw-Hill: New York. p. 595-638.

The symmetric restenosis (FIG. 2A) assumed an equal amount of neointimalhyperplasia all around the vessel, reducing the luminal diameter to 2.5mm, a cross-sectional reduction of 52% (stenosis of 48%). Inside thelumen, the model then contains a circular array of 8 electrode surfaces,each 0.15 mm in diameter, equally spaced around the neointimal tissue at45° angles from the center, an angle switch of about 45 degrees. Insidethe electrodes is a thin-walled balloon having an outer diameter ofabout 2.2 mm, modeled as rubber, and blood is assumed to be in the spacebetween the balloon and the neointima. Inside the balloon is modeled asslightly hypotonic saline. The electrical and thermal properties ofmodel components may be found in Table 1.

TABLE 1 Electrical and Thermal Properties Used in Numerical ModelingProperty Symbol Tissue Value Units Reference Electrical σ Media andAdventitia 0.25 S/m Carrara 2007 Conductivity Neointima 0.2 Carrara 2007Electrodes 4.032 × 10⁶ Metals 1990 Blood 0.7 Carrara 2007; Duck 1990Balloon    1 × 10⁻¹³ Serway 1998 Isotonic Saline (0.15M) 1.39 Gabriel2009 Density ρ Media and Adventitia 1085 kg/m³ Werner 1988 Neointima1085 Werner 1988 Electrodes 7850 Metals 1990 Blood 1059 Werner 1988Balloon 2.17 Isotonic Saline (0.15M) 1000 Kenner 1977 Thermal k Mediaand Adventitia 0.55 W/(m · K) Werner 1988; Conductivity Bhattacharya2003 Neointima 0.50 Werner 1988 Electrodes 44.5 Metals 1990 Blood 0.50Duck 1990 Balloon 0.23 Isotonic Saline (0.15M) 0.50 Specific c_(p) Mediaand Adventitia 3.20 J/(kg · K) Werner 1988 Heat Neointima 3.72 Duck 1990Capacity Electrodes 475 Metals 1990 Blood 3.84 Duck 1990 Balloon 385Isotonic Saline (0.15M) 3.84

See Carrara, N. Dielectric Properties of Body Tissues, Italian NationalResearch Council: Institute for Applied Physics, 2007 (“Carrara 2007”)cited 2010, available from: http://niremf.ifac.cnr.it/tissprop/; seealso Properties and Selection: Irons, Steels, and High-PerformanceAlloys, 10 ed. Metals Handbook, Vol. 1, 1990: ASM International (“Metals1990”); see also Duck, F. A., Physical Properties of Tissue: AComprehensive Reference Book, 1990, New York: Academic Press (“Duck1990”); see also Serway, R. A., Principles of Physics, 2nd ed.Principles of Physics, 1998, Fort Worth, Tex.; London: Saunders CollegePub (“Serway 1998”); see also Gabriel, C., A. Peyman, and E. H. Grant,Electrical conductivity of tissue at frequencies below 1 MHz, Physics inMedicine and Biology, 2009, 54(16): p. 4863-4878 (“Gabriel 2009”); seealso Werner, J. and M. Buse, Temperature profiles with respect toinhomogeneity and geometry of the human body, J Appl Physiol, 1988,65(30): p. 1110-1118 (“Werner 1988”); see also Kenner, T., H. Leopold,and H. Hinghoferszalkay, Continuous High-Precision Measurement ofDensity of Flowing Blood, Pflugers Archiv-European Journal ofPhysiology, 1977, 370(1): p. 25-29 (“Kenner 1977”); see alsoBhattacharya, A. and R. L. Mahajan, Temperature dependence of thermalconductivity of biological tissues, Physiological Measurement, 2003,24(3): p. 769-783 (“Bhattacharya 2003”).

The representative numerical model was solved for the electric fielddistribution for a voltage of 400 V/cm. This was done either with allconducting surfaces energized in an alternating (V0-0-V0) fashion aroundthe electrode, or with only two adjacent surfaces energized (one as V0and one as ground). According to embodiments of the invention, any rangeof energized wire arrangements are possible (E1 at V0 and E3 at 0; oreven E1 at V0, E4 at V0/3, and E7 at 0). Indeed, multiple electrodes canbe energized while multiple others are set to ground. There is also nolimitation on which electrodes can be energized and which are set toground, which will depend on a particular treatment protocol beingadministered. FIGS. 3A-D show the resulting electric field distributionbetween 0 and 1500 V/cm, with a black contour at 637 V/cm, a typical IREthreshold taken from the literature. See Miklavcic, D., D. Semrov, H.Mekid, and L. M. Mir, A validated model of in vivo electric fielddistribution in tissues for electrochemotherapy and for DNAelectrotransfer for gene therapy, Biochimica et Biophysica Acta, 2000,1523: p. 73-83.

The representative numerical model output of electric field (FIGS. 3A-D)and temperature (FIGS. 3E-F) is illustrated following a 100 μs pulse at400 V. More particularly, FIG. 3A illustrates treatment of symmetricrestenosis with all 8 wires energized, while FIG. 3B illustratestreatment of symmetric restenosis with only 2 wires energized. Likewise,treatment of asymmetric restenosis with all eight wires energized isshown in FIG. 3C, while treatment of asymmetric restenosis with only twowires energized is shown in FIG. 3D. The black contour line shown inFIGS. A-D is 637 V/cm.

It is important to note that the devices of the invention can compriseany number of electrically conductive wires disposed in any manner onthe electrode. In methods of the invention, any number of electricallyconductive wires can be energized in any order and in any combination.For example, for an electrode having ten electrically conductive wiresdisposed around the circumference of the electrode and spacedcircumferentially or longitudinally from one another and progressingupwardly in number order from 1 to 10, the wires can be selectivelyenergized using all, or less than all of the wires around thecircumference of the electrode or along the length of the electrode.Referring to FIG. 6A-6B, in such embodiments, wires 5 and 6 can beenergized, then wires 2 and 4 energized, then wires 3 and 5 energized totreat a target region disposed proximate the area near electrodes 2-6.This leaves the area or substantially most of the area proximate wires 6to 1 untreated.

Referring back to FIGS. 3A-3F, when all the wires of the 8-wireelectrode were energized, it was found that only the corners of theoutermost regions of the neointimal hyperplasia were not treated with637 V/cm in the symmetrical stenosis; while there is a large gap at theexpanded side in the asymmetrical case. In order to effectively treatthe entirety of the asymmetrical stenosis, significantly larger voltagesshould be used. Since previous designs would have to energize all theconducting surfaces equally, the region of tissue exposed to IRE wouldlikely expand beyond the vessel, possibly affecting healthy tissues,which highlights insufficiencies of previous catheter-based electrodedesigns regarding non-cylindrical stenoses.

Notably, when two adjacent wires were energized, the treatment marginsof IRE (presumed at 637 V/cm) extend easily through the local neointimaltissue. This shows that lower voltages may be used if pairs ofelectrodes are energized in succession rather than simultaneously.Furthermore, treating in this way allows for a practitioner to finelytune the applied voltage for each sequence, locally extending treatmentregions at thicker regions of restenosis while decreasing treatmentmargins at thinner regions. From the determination that a lower voltageis required when only two electrodes are energized at a time, it canclearly be seen how the proposed model may be used to investigate theeffects of various treatment parameters in order to optimize treatmentsto be used in clinical and pre-clinical settings.

The electric potentials used to generate the electric fields used in IREalso cause Joule heating of the tissue. This is a function of theelectric potential to which a bulk of tissue is exposed, its electricalconductivity, and the time for which it is exposed. The thermal effectsof catheter type IRE are illustrated in FIGS. 3E-F. Representativenumerical models for temperature output are illustrated for treatment ofsymmetric restenosis using all eight wires energized (FIG. 3E) and usingonly two wires energized (FIG. 3F). In order to accomplish complete IREablation of a targeted region without damaging the extracellular matrixand other sensitive structures, a comprehensive quantitativeunderstanding of the thermal effects from a treatment protocol is vital.By numerically modeling these effects, one is able to determine thepotential for any thermal damage to the tissue structures and adjusttreatment plan protocols prior to application in order to minimize oreliminate this undesired form of potential damage. Thereforequantitative modeling of the thermal effects will be done throughutilization of the numerical model previously described forunderstanding electric field behavior.

More particularly, the thermal behavior of tissue may be assessed usinga modified Pennes Bioheat equation with the addition of a Joule heatingterm as outlined below:

$\begin{matrix}{{{\nabla\left( {k{\nabla T}} \right)} + {w_{b}{c_{b}\left( {T_{a} - T} \right)}} + q^{\prime\prime\prime} + {\sigma {{\nabla\Phi}}^{2}}} = {\rho_{p}\frac{T}{c}}} & (1)\end{matrix}$

where k is the thermal conductivity of the tissue, T is the temperature,c_(b) and c_(P) are blood and tissue heat capacity, respectively, w_(b)is blood perfusion, T_(a) is arterial temperature, ρ is tissue density,σ|∇Φ|² is the joule heating term, and q′″ is metabolic heat creation.The outer vessel boundary was treated as adiabatic. See Davalos, R. V.and B. Rubinsky, Temperature considerations during irreversibleelectroporation, International Journal of Heat and Mass Transfer, 2008,51(23-24): p. 5617-5622. Because the time scale of the electroporationpulses (microseconds) is much lower than those involved in metabolicheat generation and blood flow (see Werner, J. and M. Buse, Temperatureprofiles with respect to inhomogeneity and geometry of the human body, JAppl Physiol, 1988, 65(30): p. 1110-1118; and Gautherie, M., Y.Quenneville, and C. M. Gros, Metabolic heat production, growth rate, andprognosis of early breast carcinomas, Biomedicine, 1975, 22: p.328-336), one is able to see that the dominant terms affecting change intemperature for a volume of tissue is the contributions of heatconduction from neighboring tissues and electroporation pulse inducedJoule heating.

By eliminating the blood perfusion and metabolic heat generation termsand rearranging the terms, the equation becomes:

$\begin{matrix}{\frac{T}{t} = \frac{{\nabla\left( {k{\nabla T}} \right)} + {\sigma {{\nabla\Phi}}^{2}}}{\rho \; c_{p}}} & (2)\end{matrix}$

For a single pulse of infinitely small duration, δt, the change intemperature may be described by:

$\begin{matrix}{{dT} = {\begin{matrix}{{\nabla\left( {k{\nabla T}} \right)} + {\sigma {{\nabla\Phi}}^{2}}} \\{oc}_{p}\end{matrix}{t}}} & (3)\end{matrix}$

From the modified Pennes' Bioheat equation above, it becomes evidentthat the controllable terms affecting electroporation-inducedtemperature changes are the magnitude of the electric field and theduration of the pulse. Assessment of thermal effects from the modelwould allow one to adjust the protocols to prevent thermal damage andunderstand its impact on the electric field distribution. For instance,the pulse length could be shortened, a low-conductivity gel could beinjected into the tissue, or an actively-cooled electrode could be usedto cool the tissue prior to and during pulsing.

The representative numerical model of FIGS. 3A-F has been evaluated forthe temperature distribution resulting from a single 100 μs pulse. Theinitial condition for the temperature of the entire tissue was taken tobe 310.15 K (37° C.), which is the physiological temperature. FIGS. 3E-Fshow the results when a voltage of 400 V was applied to the symmetricstenosis for the case of eight and two energized surfaces. From this, itcan be seen that only a very small portion of blood near the electrodesreaches temperatures above 314 K, a change of 4 K. In addition, most ofthe thermal effects occur in the blood between the energized surfaces,with very little noticeable effect to the neointimal tissue.

To evaluate potential thermal damage, the maximum temperature could becompared to a typical threshold of protein denaturation and scarring of50° C. (323 K). See Diller, K. R., Advances in Heat Transfer, inBioengineering Heat Transfer, Y. I. Choi, Editor, 1992, Academic PressBoston. p. 157-357. Because 316 K falls well below this temperaturethreshold, it is clear that the treatment protocols used in the firstpart of this numerically modeled example are able to fully treat thetargeted region without inflicting thermal damage. It should be notedthat thermal damage may occur at temperatures below 50° C. when carriedout over a long period of time (such as hours, for example), and thatthe combined effects of many pulses may further increase thetemperatures. However, for the current example of the numerical modeloutlined above, it may be assumed that the high perfusion rate of bloodin an artery will rapidly dissipate the heat generated. In embodiments,however, where the balloon is inflated blood flow within the bloodvessel may be greatly reduced or completely blocked and heat dissipationmay occur in some other manner. This, in addition to the relatively longspan between pulses (for example, meaning 0.25 seconds as compared to0.0001 seconds of a 100 μs long pulse); allows one to expect that thetemperature will return to physiologic temperatures prior to the nextpulse, preventing it from ever exceeding the 50° C. threshold.

A method of selectively ablating asymmetric restenosis is illustrated inFIG. 4. Such methods can involve one or more of the following: insertinga balloon catheter electrode in a blood vessel; imaging the body inwhich the catheter is placed, for example, using ultrasound, x-ray, CT,MRI, etc.; based on the imaging results, determining which electricallyconductive wires of the electrode are near the restenosis; determiningwhich wires of the electrode to energize and the magnitude of theelectrical charge needed to treat the target tissue; and delivering anIRE type electrical charge(s) between the selected wires of theelectrode to ablate the restenotic tissue. These method steps can beused singularly or one or more together with other methods and/or methodsteps described in this specification. One of skill in the art will knowhow to modify the methods according to a particular result to achieve.

Methods of the invention can also include the capability of being ableto synchronize the electrical pulses with the cardiac rhythm of thepatient to avoid arrhythmia. This is especially important for treatmentsadministered on coronary arteries, e.g., directly at the heart, wherechances of arrhythmia are highest. In addition, treatment ofarrhythmogenic regions of the heart from the inside is yet anotherapplication for the asymmetric ablation protocols of the presentinvention. In some situations, it is feasible that such treatments couldbe used in lieu of open heart surgery.

Preferred methods of embodiments of the invention are directed toelectrically ablating tissue, with the method comprising: inserting intoa vessel an electrode having a plurality of electrically conductivewires disposed lengthwise along the electrode and circumferentiallyspaced a selected distance from one another; orienting the electrodewithin the vessel to provide one or more of the electrically conductivewires in position to deliver one or more electrical pulse to targettissue; selecting one or more but less than all of the electricallyconductive wires for administering the electrical pulse(s);administering the electrical pulse(s) from the selected electricallyconductive wires to deliver the electrical pulse(s) to the target tissueand less than all vessel circumference; and wherein the administering isperformed for a time and under circumstances sufficient to causeirreversible electroporation of the target tissue or a portion thereof.

Methods of the invention can also be used for reversible electroporationof tissue to assist or enable electrochemotherapies and/orelectrogenetherapies. Even further, aspects of methods of the inventioninclude inserting the electrode device into any organ or vessel which isnot in particular a blood vessel, such as within the lymphatic systemfor treating undesired tissue such as lymphoma. Even further, theelectrodes can be used in arrhythmogenic regions of the heart or tumornodules in the lungs, which can be accessed through vessels of therespiratory tract such as bronchial tubes or blood vessels.

Methods of the invention can employ an electrode comprising a flexiblecatheter and inflatable balloon with the electrically conductive wiresdisposed lengthwise along and circumferentially spaced around theelectrode, such as on a surface of the inflatable balloon.

In embodiments, the electrically conductive wires can be selectivelyenergized, especially in a sequential manner across only a portion ofthe circumference of a blood vessel or other treatment area. Forexample, in embodiments where an electrode comprises eight electricallyconductive wires, the method can comprise orienting only a portion ofthe wires proximate a target treatment area, such as wires 1, 2, and 3of the eight-wire system. A selected number of pulses at a selectedelectrical charge can be administered between wires 1 and 2, then aselected number of pulses at a selected electrical charge (which may bedifferent or the same as that applied between wires 1 and 2) may bedelivered between wires 2 and 3. Then this pattern or a differentpulsing protocol can be administered selectively and sequentially usingselected wire pairs. In preferred embodiments, less than all of the wirepairs are used and less than all of the circumference of the electrodeis energized during a treatment. In this manner, less than all of thesurface area of a blood vessel can be subjected to the IRE.

More particularly, for example, 10 pulses of 50 μs in length at 500 V/cmcan be delivered between a first selected electrically conductive wirepair, then 100 pulses of 100 μs in length at 2500 V/cm can be deliveredusing a second wire pair, then 50 pulses at 75 μs in length at 1000 V/cmcan be administered using a third wire pair. This sequence of pulsingcan then be repeated any number of times until a desired treatmentoutcome is reached. Alternatively, any one or more of the pulsingparameters can be changed during the treatment to modify the effect thepulsing protocol is having on the tissue. For example, a second round ofpulsing using the first, second, and third wire pairs can beadministered by changing the parameters for the third wire pair, such asby delivering 20 pulses that are 90 μs in length at 1500 V/cm. Thisround of pulsing protocols, or combinations of the protocols, can thenbe continuously and sequentially administered until a desired treatmentresult is achieved. By energizing only a portion of the circumference ofthe electrode (only the first, second, and third wire pairs), only aportion of a selected region of the body that surrounds the electrode,such as a portion of a blood vessel, is subjected to the IRE thusrendering the non-targeted regions unaffected. Changing parametersimpacts the depth of IRE ablation. Accordingly, the treatment can becustomized to ensure complete treatment of thicker stenotic segmentswithout over-treating regions with shallower stenotic segments.

FIG. 5 is a schematic diagram illustrating a representative electricalcircuit for an electroporation system according to embodiments of theinvention. More particularly, FIG. 5 provides a schematic of anelectrical circuit for an electroporation system, the system comprisinga plurality of electrically conductive wires (electrodes) or solutionswith high electrical conductivity (blood); a pulse generator andsensor(s) in operable communication with the probes; and a controller orcontrol system in operable communication with the pulse generator andsensor(s). The controller in operable communication with the othercomponents of the system together provide for a system capable ofselective electrode energizing. The electrical circuit 10, inparticular, comprises an electrical connection with a power source fordelivery of electrical energy to the controller 71. The controller 71,alone or in combination with sensor(s) 73, in turns provides power tothe pulse generation circuit 72. The pulse generation circuit 72 is inoperable communication with a switch for delivering the electricalenergy to one or more, all, or less than all of the probes. The switchis operably configured to selectively deliver electrical energy to theprobes in any manner. In preferred embodiments, the switch is capable ofproviding electrical energy sequentially to each of the probes over theentire circumference of the electrode, or over only a portion of thecircumference of the electrode. Likewise, the switch is capable ofproviding electrical energy to a single probe, or more than one probe,or combinations of any two probes, in combination with any pulseprotocol using any number, or length, or intensity of electrical pulses.The switch and pulse generator are operably connected with any number ofprobes. Here, up to eight probes or electrically conductive wires areillustrated for this representative system.

As shown in FIGS. 6A-G, other aspects of embodiments of the inventioninclude devices and methods for determining the identification, locationand/or orientation of the electrode and/or electrically conductive wireswhen inserted into the body, and especially with respect to the locationof target tissue, including asymmetrical stenosis in a blood vessel.

A representative embodiment is provided in FIGS. 6A-G. By equippingdevices and systems of the invention with one or more imaging markers,the overall rotational orientation of the electrode as disposed in abody or vessel can be determined. As shown in FIG. 6A, an angioplastyballoon type catheter electrode can comprise six electrically conductivewires disposed longitudinally over the length of the electrode andcircumferentially spaced a selected distance from one another around thecircumference of the catheter or electrode. FIG. 6B, shows briefradio-opaque plugs (such as silver) provided on or in connection withone or more or all of the electrically conductive wires of theelectrode. Here, an imaging marker is associated with each of theelectrically conductive wires and is disposed in the electrode in amanner to provide the plugs progressing clockwise/counterclockwisearound the wires of the electrode. The schematic of FIG. 6B provides across-sectional view of the device illustrating placement of the imagingmarkers in connection with the electrically conductive wires.

Although a 6-wire system is provided in FIGS. 6A-G, the approach couldbe used with any number of wires by altering the angle switch from each.In the context of this specification, the term “angle switch” is meantto refer to the angular distance of separation between electricallyconductive wires around the circumference of the electrode. For example,an electrode with four wires would have an angle switch of about 90degrees between wires, while an electrode with six wires has an angleswitch of about 60 degrees. In preferred embodiments, electrodes of theinvention comprise any number of electrically conductive wires rangingfrom 1 to 20, such as from 2-10, or from 4-8, or even from 5-6 wires.The wires can also be disposed in any orientation relative to theelectrode, such as circumferentially and longitudinally spaced aselected distance from one another; or disposed longitudinally andspaced circumferentially a selected distance from one another; or theelectrically conductive wires can be disposed in a spiral or helicalmanner around the circumference of the electrode.

Additionally, or alternatively, proximal and distal imaging markers canbe provided at one or both ends of the electrode device. In preferredembodiments, the proximal and distal markers can comprise a radio-opaquematerial with an overall annular shape for disposing each imaging markeraround the circumference of the electrode/catheter (to give a definitivestart and finish).

With the electrode device inserted into the body of a patient, theregion of the body where the device is disposed can be imaged, forexample, using x-ray, ultrasound, MRI, CT, or angiography, for example.Depending on the shapes that show up on angiography/x-ray, theorientation of the electrode within the body can be determined,especially its rotational orientation within a blood vessel and relativeto a stenotic region. In embodiments, any number of imaging markers canbe used, such as from 1-25 and any number in between. In preferredembodiments, at least two markers are used, such as one marker to denoteeach electrically conductive wire. By measuring the 2D distance from oneimaging marker to the next as revealed on an imaging modality, therotation of the electrode can be determined.

Further, in embodiments, a differential echogenicity (extra bright/darkin ultrasound) can be placed at the distal tip and proximal portions atone or more specific electrically conductive wires so that the markercould be picked up on intravascular ultrasound (IVUS). Using theseapproaches, it is relatively easy to see wire orientations relative toany asymmetrical stenoses or other targets.

FIG. 6C illustrates an electrode embodiment of the invention comprisingsix electrically conductive wires, each with an associated imagingmarker disposed on, proximal to, or in connection therewith. In thisembodiment, the imaging markers for the electrically conductive wiresare radio-opaque plugs disposed in a counterclockwise progressivemanner, which are used to denote the location of each wire. Proximal anddistal end imaging markers are also included, which show where the wireimaging markers begin and end. Optionally included is a hyperechoic slugdisposed in association with wire 1. As illustrated, represented is theexpected x-ray image of the balloon catheter electrode of FIG. 6Ainserted in a body and disposed within the vessel in a plane parallel tothe drawing sheet.

FIGS. 6D-G provide representative x-ray images of the electrode disposedat a rotational orientation relative to that shown in FIG. 6C. Moreparticularly, as shown in FIG. 6D, the image illustrates the ballooncatheter disposed in a body in same orientation as shown in FIGS. 6A and6C. The representative x-ray image of FIG. 6E, indicates the ballooncatheter electrode is oriented in the body with wire 1 oriented uptoward and closest to the imaging device. Further, the orientation ofthe device of FIG. 6E is rotated upward out of the plane of the drawingsheet and 90 degrees relative to the position shown in FIGS. 6A, 6C, and6D. If the device were then rotated another 90 degrees upward from theposition shown in FIG. 6E, the imaging markers would be arranged asillustrated in FIG. 6F. Similarly, FIG. 6G shows rotation of the deviceanother 90 degrees upward from the position shown in FIG. 6F, withmarker 1 farthest from the imaging device, thus indicating wire 1 is 180degrees rotated from the source of the imaging device.

Another embodiment can comprise a radio-opaque spiral rotating in acertain direction from a specific wire. The direction where it rotatesfrom and ends on would give an exact orientation of the catheter.

In yet other embodiments, it is possible to use the wires themselves toidentify which are the closest to the restenosis site for purposes ofdetermining which electrodes to energize to treat a targeted area withinthe vessel. For example, using an electrical charge, anon-electroporating test signal (AC or DC pulse or pulses) can beinjected between a pair of wires. Then, the electrical characteristicsof the tissue lying between the electrode pair can be measured. Theelectrical characteristics measured can include, for example,resistance, impedance (complex impedance which includes real andimaginary parts), electrical impedance tomography, and so forth. Themeasured characteristics of healthy tissue will be different from thatof restenotic tissue. The measured characteristics can thus be comparedwith threshold electrical characteristics determined by experiment, suchas shown in U.S. Pat. No. 7,742,795, issued Jun. 22, 2010 to MinnowMedical Inc., incorporated herein by reference.

FIGS. 6H-M illustrate another of many potential ways to determine exactrotational orientation of the catheter electrode to ensure thatdifferential targeting occurs in the desired region of the blood vessel.This example provides an 8-conducting wire electrode with a simplesystem of 2 radiopaque markers oriented 90 degrees apart (wires 1 and3). The system would be appropriate for use with angiography, and themarkers could be placed on the balloon below the electrodes, using amore radiopaque marker than the conducting wires themselves, such assilver. Including a circumferential marker in the device ensuresstarting at the correct wire (more useful for applications such as ifevery wire were to have a marker).

As shown, the imaging markers in this embodiment are different sizes toidentify each marker and differentiate between the two. Here, wire 1'smarker is long and wire 3's marker is short. This configuration allowsthe markers to overlap in length so the distance between the two can beeasily measured to get an exact angle of rotation. A schematic providinga cross-sectional view and a side view of the device as it would appearas an image on an imaging device is shown in FIG. 6H. It is noted thatin FIGS. 6H-M that the illustrations are not intended to representexactly how the images would actually look on for example angiography(because more radiopaque materials show up darker), rather theschematics are intended to show how the position of the markers wouldidentify the orientation of the device.

FIG. 6I illustrates how the electrode would look on angiography orientedwith conducting wire 1 on top (assuming balloon and wires invisible toscanner); FIG. 6J illustrates the electrode oriented with conductingwire 1 on bottom; FIG. 6K illustrates electrode orientation withconducting wire 1 on right (relative to electrode direction); FIG. 6Lillustrates the electrode orientation with conducting wire 1 at 10:30orientation (relative to electrode direction); and FIG. 6M illustrateshow the would look on angiography oriented with conducting wire 1 at2:30 orientation (relative to electrode direction)—distance measuredbetween the two markers will give the amount of angle electrode.

Determining the proximity of each wire to the restenotic region ispossible due to the differences in impedance between restenotic tissue(densely packed disorganized cells) and blood vessel walls (endotheliallayer surrounded by connective tissue). In embodiments, a sequence ofnon-electroporating electrical test pulses (AC or DC) between any one ormore, or all, conducting wire pairs around the perimeter of the cathetercould be used to determine the extent/depth of restenosis between eachpair in real-time while the balloon is inside the tubular body part.This data could then be used to generate a “map” of restenosis deptharound the electrode. This data can further be used to generate aprotocol for how strong the electrical pulses should be between eachwire pair to ablate all of the restenosis for that portion of thevessel. In other words, greater restenosis depth between electrode pairswould have a greater change in properties, which would guide thepractitioner to use higher voltages for that pair to ensure ablation ofthe entire depth, while areas without as much depth would warrantelectrical pulses of lower voltage(s). Accordingly, a machine/programcould be used to automatically customize pulse parameters for each pairbased on restenosis geometry.

In one embodiment, the treatment control module 54 has been programmedto display on the display device 11 a graphical representation of thestenosis and a graphical representation and identification of theelectrodes (e.g., electrode numbers) in positional relationship to thestenosis. Graphically, the image would be similar to that shown in FIG.2B, except the electrodes would be numbered such that a user would beable to judge for himself which electrodes are closest to the stenosissite as well as the depth of the stenosis for each pair of electrodes.After displaying the graphical images, the treatment control module 54would then select the proper electrodes pairs to energize and theelectrical parameters for the selected pair as the protocol. Forexample, in FIG. 2B, assume that electrodes starting from the one at 12o'clock position, clock-wise, are numbered 1 through 8. In that case,the selected electrodes may be pair 0-1, 1-2, 2-3 and 3-4. The selectedvoltages for the pairs may be 500 V/cm for pairs 0-1 and 3-4, and 1200V/cm for pairs 1-2 and 2-3. Alternatively, the voltage may be the samefor all selected pairs, but the number of pulse repetition may begreater for pairs 1-2 and 2-3 since a larger ablation region can beobtained with a larger number of pulses applied. Alternatively, thepulse duration may be greater for pairs 1-2 and 2-3. The treatmentcontrol module 54 then displays on the display device 11 the determinedprotocol for the user to change or accept. The treatment control module54 allows the user to change the electrode pairs and other electricalparameters such as voltage, pulse duration and number of repetition foreach pair. Preferably, each pulse is a biphasic pulse. To ensure thatthe thermal damage, if any, is minimized, the treatment control module54 may apply a few pulses to one pair, apply some pulses to anotherpair, and then come back to the original pair to apply remaining pulses.

For example, the module 54 may control the switch to electricallyenergize pair 0-1 for 10 times, 3-4 for 10 times, 1-2 for 10 times, 2-3for 10 times, and then repeat the same pattern for 10 times for a totalnumber of 100 repetition for each electrode pair.

Even in such an embodiment, it is preferred to have 2-3 radio-opaquemarkers as well as at least one intravascular ultrasound markerincluded, especially in cases where a catheter style electrode is usedfor applications beyond restenosis ablation, such as a minimallyinvasive method for targeting ablation/Electrochemotherapy/gene transferin a region of tissue between two vessels. In such a protocol, onecatheter style electrode can be inserted into a first vessel and asecond catheter style electrode is inserted into a second vesselproximal in location to the first vessel. Targeting the tissue betweenthe vessels for ablation, wire(s) facing each other from each cathetercan be energized to target the tissue in this region. Preferably, onlythe wires facing each other are energized so that surrounding tissue isnot affected.

FIG. 7 is a schematic diagram illustrating an IRE system of theinvention as disclosed more fully in PCT Patent Application No.PCT/US10/29243, filed Mar. 30, 2010 and entitled “System and Method forEstimating a Treatment Region for a Medical Treatment Device and forInteractively Planning a Treatment of a Patient”, incorporated herein byreference. As illustrated, representative systems can comprise acomputer 40 comprising or in operable communication with a computerprogram embodied in a computer-readable storage medium, which programwhen executed, enables the computer to operate an IRE medical device.The computer 40 is in operable communication with a mouse 14, keyboard12, and monitor 11 to enable a user to operate the IRE system.Optionally, computer 40 is in operable communication with one or moreimaging modality 30, such as an x-ray, for identifying target tissue ina patient 15 and/or identifying the orientation of electrodes insertedinto patient 15. Target tissue 300 (but also inserted electrodes 300)can be viewed on the screen 31 of imaging device 30, as well as onmonitor 11. During an IRE procedure, the IRE treatment area 301 can beviewed on monitor 11. Computer 40 is also in operable communication withan electrical pulse generator 10, which in turn is in operablecommunication with electrodes 22. Any electrical connection betweencomponents of the system can be used, as for example a USB connectioncan be used to connect the computer 40 with electrical charge generator10.

In specific embodiments, an intravascular IRE system is providedcomprising: one or more intravascular catheter type electrode 22 havingan inflatable balloon and a plurality of electrically conductive wiresdisposed lengthwise along the electrode and circumferentially spaced aselected distance from one another; an electrical pulse generator 10 inoperable communication with and for delivering electrical pulses to theplurality of electrically conductive wires of the electrodes 22; and acontrol system 40, 30 in operable communication with the electricalpulse generator 10 comprising a computer program embodied in acomputer-readable storage medium, which program when executed, enables acomputer 40 to perform a method comprising: determining orientation ofthe wires of the electrode relative to target tissue 300; selecting oneor more but less than all of the electrically conductive wires foradministering the electrical pulse(s); and energizing the selected wiresto deliver the electrical pulse(s) to the target tissue 300.

FIG. 8 is a schematic diagram illustrating a control system forimplementing methods of the invention and/or operating systems anddevices of the invention. Representative embodiments of control systems40 of the invention can include a computer or computer system with acentral processing unit (CPU) 46. The computer system 46 is in operablecommunication with a power source 52 for supplying electrical power torun the computer, which power supply is controlled using an on/offswitch 42. The CPU 46 is operationally connected with one or morecomputer programs 48 for operating an IRE device or system of theinvention. The computer program 48 can comprise instructions 54 forimplementing treatment procedures of the invention. By way of connection53, CPU 46 is in operable communication with memory 44 and one or moredata storage device 50. Together, the CPU 46, memory 44, and datastorage 50 run computer program(s) 48/54 to operate IRE systems ordevices of the invention according to one or more of the methodsdescribed in this specification. One or more input devices 12, 14 are inoperable communication with the computer system 40 to provideinformation needed for implementing the treatment protocols. Forexample, input devices 12, 14 could include one or more imagingmodalities to provide information to the practitioner about the targetregion of interest of a patient, such as shape and size of a tumor orrestenosis, or information about the orientation of an electrode in apatient, especially with respect to orientation of certain electricallyconductive wires of the electrode relative to a target region ofinterest. The imaging modalities can include for example MRI, CT, orx-ray. Another such input device 12, 14 could include sensors forcollecting information about the tissue being treated, such as currentor conductance information. One or more display device 11, such as amonitor, can also be operationally connected with systems of theinvention for the practitioner to be able to view the target region ofinterest and/or positioning or orientation of electrodes in a patient.

The present invention has been described with reference to particularembodiments having various features. In light of the disclosure providedabove, it will be apparent to those skilled in the art that variousmodifications and variations can be made in the practice of the presentinvention without departing from the scope or spirit of the invention.One skilled in the art will recognize that the disclosed features may beused singularly, in any combination, or omitted based on therequirements and specifications of a given application or design. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention.

For example, the device and method described herein may be used to treatother types of lesions such as aneurysm of a blood vessel.

It is noted in particular that where a range of values is provided inthis specification, each value between the upper and lower limits ofthat range is also specifically disclosed. The upper and lower limits ofthese smaller ranges may independently be included or excluded in therange as well. The singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. It is intendedthat the specification and examples be considered as exemplary in natureand that variations that do not depart from the essence of the inventionfall within the scope of the invention. Further, all of the referencescited in this disclosure are each individually incorporated by referenceherein in their entireties and as such are intended to provide anefficient way of supplementing the enabling disclosure of this inventionas well as provide background detailing the level of ordinary skill inthe art.

1. A method of treating a stenosis of a tubular body part by non-thermalirreversible electroporation comprising: inserting, through the tubularbody part, a balloon catheter having at least three electrodespositioned and spaced apart along the balloon, the electrodes beingelectrically independent from each other; expanding the balloon to bringthe electrodes near a stenosis to be treated; determining whichelectrodes are near the stenosis; applying electrical pulses to theelectrodes according to the determination of which electrodes are nearthe stenosis, the applied pulses being in an amount which is sufficientto induce irreversible electroporation of cells of the stenosis, butwhich is insufficient to induce thermal damage to substantially all ofthe cells of the stenosis such that substantially all stenosis cells arekilled by non-thermal irreversible electroporation.
 2. The method ofclaim 1, wherein the step of applying electrical pulses includesselecting at least one electrode to which the electrical pulses are notto be applied.
 3. The method of claim 1, wherein the step of applyingelectrical pulses includes connecting through a switch a pulse generatoroutput to any pair of the electrodes independent of the otherelectrodes.
 4. The method of claim 3, wherein the step of applyingelectrical pulses includes control the switch to output the electricalpulses to only those electrodes that have been selected based on adetermination of which electrodes are near the stenosis.
 5. The methodof claim 1, further comprising determining at least one individualizedelectrical parameter for each pair of electrodes based on thedetermination of which electrodes are near the stenosis.
 6. The methodof claim 5, wherein the at least one electrical parameter includesVoltage or pulse duration.
 7. The method of claim 1, further comprisingdetermining at last one individualized electrical parameter for eachpair of electrodes based on the depth and proximity of the stenosis inrelation to the electrode positions.
 8. The method of claim 7, whereinthe step of determining at least one individualized electrical parameterincludes determining an individualized voltage level to use for eachpair of electrodes based on the depth of the restenosis near the eachpair.
 9. The method of claim 1, wherein which electrodes are near thestenosis is determined by one or more imaging markers disposed near theelectrodes.
 10. The method of claim 9, wherein the one or more imagingmarkers include a radiopaque marker.
 11. The method of claim 1, whereinwhich electrodes are near the stenosis is determined by applying testpulses to different pairs of the electrodes and measuring at least oneelectrical characteristic of the stenosis cells for the different pairsof electrodes.
 12. The method of claim 11, wherein the step ofdetermining includes measuring an electrical resistance as the at leastone electrical characteristic of tissue cells.
 13. The method of claim12, further comprising displaying a graphical representation andidentification of the electrodes in positional relationship to thestenosis.
 14. The method of claim 12, further comprising displaying agraphical representation of the stenosis and a graphical representationand identification of the electrodes in positional relationship to thestenosis.
 15. A medical device for treating a stenosis of a tubular bodypart by non-thermal irreversible electroporation comprising: a pulsegenerator adapted to generate electrical pulses in an amount which issufficient to induce irreversible electroporation of cells of a stenosisto be treated, but which is insufficient to induce thermal damage tosubstantially all of the cells of the stenosis; a catheter; a balloonattached to a distal portion of the catheter; at least three electrodespositioned and spaced apart along the balloon, and electricallyindependent from each other, the electrodes adapted to receive theelectrical pulses from the pulse generator such that substantially allof the cells of the stenosis are killed by non-thermal irreversibleelectroporation.
 16. The medical device of claim 15, further comprisinga switch connected between a pulse generator and the electrodes, andadapted to connect the pulse generator output to any pair of theelectrodes independent of the other electrodes.
 17. The medical deviceof claim 16, further comprising a treatment control module adapted tocontrol the switch to output the electrical pulses to those electrodesthat have been selected based on a determination of which electrodes arenear the stenosis.
 18. The medical device of claim 15, wherein thetreatment control module is adapted to determine at least oneindividualized electrical parameter for each pair of electrodes based ona determination of which electrodes are near the stenosis.
 19. Themedical device of claim 18, wherein the at least one electricalparameter includes Voltage or pulse duration.
 20. The medical device ofclaim 17, further comprising one or more imaging markers disposed nearthe electrodes to determine which electrodes are near the stenosis. 21.The medical device of claim 20, wherein the one or more imaging markersinclude a radiopaque marker.
 22. The medical device of claim 17, whereinthe treatment control module is adapted to determine which electrodesare near the stenosis by applying test pulses to different pairs of theelectrodes and measuring at least one electrical characteristic of thestenosis cells for the different pairs of electrodes.
 23. The medicaldevice of claim 22, wherein the treatment control module is adapted tomeasure an electrical resistance as the at least one electricalcharacteristic of tissue cells.
 24. The medical device of claim 23,wherein the treatment control module is adapted to display a graphicalrepresentation and identification of the electrodes in positionalrelationship to the stenosis.
 25. The medical device of claim 23,wherein the treatment control module is adapted to display a graphicalrepresentation of the stenosis and a graphical representation andidentification of the electrodes in positional relationship to thestenosis.
 26. The medical device of claim 15, wherein the treatmentcontrol module is adapted to determine at least one individualizedelectrical parameter for each pair of electrodes based on the depth andproximity of the stenosis in relation to the electrode positions. 27.The medical device of claim 15, wherein the treatment control module isadapted to determine an individualized voltage level to use for eachpair of electrodes based on the depth of the stenosis near each pair.28. A method for treating a lesion of a tubular body part by non-thermalirreversible electroporation comprising: inserting into the tubular bodypart a plurality of elongated electrodes disposed lengthwise andcircumferentially spaced a selected distance from one another;positioning the electrodes within the tubular body part to provide oneor more of the electrodes in position to deliver a plurality ofelectrical pulse to a target lesion; selecting electrodes among theplurality of electrodes for administering the electrical pulses;administering the electrical pulses through only the selected electrodesto the target lesion in an amount which is sufficient to induceirreversible electroporation of cells of the target lesion, but which isinsufficient to induce thermal damage to substantially all of the cellsof the target lesion such that substantially all cells of the targetlesion are killed by non-thermal irreversible electroporation.
 29. Themethod of claim 28, wherein the electrode comprises a flexible catheterand inflatable balloon and the electrodes are disposed lengthwise alongand are circumferentially spaced around a surface of the inflatableballoon.
 30. The method of claim 28, further comprising determining anorientation of the electrode within the tubular body part by imaging,wherein the electrode comprises at least one imaging marker fordetermining location of the electrodes.
 31. The method of claim 30,further comprising measuring a distance between the imaging markers andusing the distances to calculate rotational orientation of theelectrode.
 32. The method of claim 30, wherein the at least one markeris radio-opaque.
 33. The method of claim 32, wherein at least tworadio-opaque markers and at least one intravascular ultrasound markerare provided on or near an inflatable balloon.
 34. The method of claim28, wherein the step of selecting electrodes includes: administering oneor more test pulses through any one or more of pairs of the electrodes;determining from the test pulses one or more electrical characteristicsof tissue subjected to the test pulses and based on the electricalcharacteristics further determining a depth of the target lesion; andgenerating a protocol for administering higher voltage electrical pulsesbetween electrode pairs positioned for treating a deep lesion area andfor administering lower voltage electrical pulses between electrodepairs positioned for treating a shallow lesion area.